CC-1065, the duocarmycins, and yatakemycin constitute exceptionally potent naturally occurring antitumor agents that derive their biological properties through a characteristic sequence-selective DNA alkylation reaction (below) (Chidester, C. G.; et al. J. Am. Chem. Soc. 1981, 103, 7629; Trzupek, J. D.; et al. Nature Chem. Biol. 2006, 2, 79).

The examination of the natural products, their synthetic unnatural enantiomers, their derivatives, and synthetic analogues have defined fundamental features that control the alkylation selectivity, impact the alkylation efficiency, and are responsible for DNA alkylation catalysis providing a detailed understanding of the relationships between structure, reactivity, and biological activity (Warpehoski, M. A.; Hurley, L. H. Chem. Res. Toxicol. 1988, 1, 315; Boger, D. L. Chem. Biol. 2004, 11, 1607.).
One of the most important and widely explored class of analogues is CBI (Boger, D. L.; et al. J. Am. Chem. Soc. 1989, 111, 6461; Boger, D. L.; et al. J. Org. Chem. 1990, 55, 5823) (1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one), being synthetically (Boger, D. L.; et al. J. Am. Chem. Soc. 1989, 111, 6461; Boger, D. L.; et al. J. Org. Chem. 1990, 55, 5823; Boger, D. L.; et al. J. Org. Chem. 1992, 57, 2873; Boger, D. L.; McKie, J. A. J. Org. Chem. 1995, 60, 1271; Drost, K. J.; Cava, M. P. J. Org. Chem. 1991, 56, 2240; Aristoff, P. A.; Johnson, P. D. J. Org. Chem. 1992, 57, 6234; Mohamadi, F.; et al. J. Med. Chem. 1994, 37, 232; Ling, L.; et al. Heterocyclic Commun. 1997, 3, 405; Boger, D. L.; et al. Synlett 1997, 515; Boger, D. L.; et al. Tetrahedron Lett. 1998, 39, 2227; Kastrinsky, D. B.; Boger, D. L. J. Org. Chem. 2004, 69, 2284) more accessible than the natural products, yet indistinguishable in their DNA alkylation selectivity (FIG. 2) (Boger, D. L.; Munk, S. A. J. Am. Chem. Soc. 1992, 114, 5487).
Moreover, the CBI derivatives proved to be four times more stable and, correspondingly, four times more potent than derivatives bearing the CC-1065 alkylation subunit (7-MeCPI) approaching the stability and potency of duocarmycin SA and yatakemycin derivatives, and they exhibit efficacious in vivo antitumor activity in animal models at doses that reflect this potency (Boger, D. L.; et al. Bioorg. Med. Chem. Lett. 1991, 1, 115; Boger, D. L.; et al. Bioorg. Med. Chem. 1995, 3, 1429). Consequently, CBI and its derivatives have been the focus of much development as well as the prototype analogues on which new design concepts have been explored, developed, or introduced (Boger, D. L.; et al. J. Am. Chem. Soc. 1989, 111, 6461; Tietze, L. F.; et al. Angew. Chem. Int. Ed. 2006, 45, 6574; Wang, Y.; et al. Bioorg. Med. Chem. 2003, 11, 1569; Jeffrey, S. C.; et al. J. Med. Chem. 2005, 48, 1344; Kline, T.; et al. Mol. Pharmaceut. 2004, 1, 9; Hay, M. P.; et al. J. Med. Chem. 2003, 46, 5533; Tercel, M.; et al. J. Med. Chem. 2003, 46, 2132; Gieseg, M. A.; et al. Anti-Cancer Drug Design 1999, 14, 77; Hay, M. P.; et al. Bioorg. Med. Chem. Lett. 1999, 9, 2237; Atwell, G. J.; et al. J. Med. Chem. 1999, 42, 3400; Atwell, G. J.; et al. J. Org. Chem. 1998, 63, 9414; Atwell, G. J.; et al. Bioorg. Med. Chem. Lett. 1997, 7, 1493; Townes, H.; et al. Med. Chem. Res. 2002, 11, 248; Boger, D. L.; Garbaccio, R. M. J. Org. Chem. 1999, 69, 8350).
A unique feature of this class of molecules including the natural products themselves is the observation that synthetic phenol precursors (e.g., 1) to the final products, entailing a Winstein Ar-3′ spirocyclization with displacement of an appropriate leaving group, exhibit biological properties typically indistinguishable from the cyclopropane-containing final products (DNA alkylation rate or efficiency, in vitro cytotoxic activity, and in vivo antitumor activity). This dependable behavior of the precursor phenols has provided the basis on which the development of useful, stable, or safe prodrugs has been conducted (Carzelesin: Aristoff, P. A. Adv. Med. Chem. 1993, 2, 67. KW-2189: Kobayashi, E.; et al. Cancer Res. 1994, 54, 2404; Amishiro, N.; et al. Bioorg. Med. Chem. 2000, 8, 1637; Amishiro, N.; et al. J. Med. Chem. 1999, 42, 669; Nagamura, S.; et al. Chem. Pharm. Bull. 1996, 44, 1723; Nagamura, S.; et al. Chem. Pharm. Bull. 1995, 43. CBI: Boger, D. L.; et al. Synthesis 1999, 1505).
One feature limiting the attractiveness of this class of cytotoxic agents is their remarkable potencies (IC50 5-20 pM) creating special requirements for their preparation and handling. In many instances, this has been addressed by the introduction of chemically stable phenol protecting groups that are readily cleaved at the final stage of their preparation or upon in vivo administration. Such protected phenol precursors are intrinsically much less potent, yet readily release an active precursor to the drug upon deprotection. Extensions of this protection and release strategy have been pursued in which the free phenol release in vivo is coupled to features that might facilitate tumor selective delivery or cleavage (Wolkenberg, S. E.; Boger, D. L. Chem. Rev. 2002, 102, 2477. Reviews on reductive activation: Papadopoulou, M. V.; Bloomer, W. D. Drugs Future 2004, 29, 807; Jaffar, M.; Stratford, I. J. Exp. Opin. Ther. Patents 1999, 9, 1371; Patterson, L. H.; Raleigh, S. M. Biomed. Health Res. 1998, 25, 72). Such inactive prodrugs serve the dual role of providing safer handling intermediates or final products as well as potentially enhancing the therapeutic index of the drug.
As attractive and amenable as this approach is for this class of drugs, a surprisingly small series of such studies have been disclosed (Chari, R. V. J.; et al. Cancer Res. 1995, 55, 4079; Lillo, A. M.; et al. Chem. Biol. 2004, 11, 897; Tietze, L. F.; et al. Eur. J. Org. Chem. 2002, 10, 1634; Tietze, L. F.; et al. Angew. Chem. Int. Ed. 2002, 41, 759; Tietze, L. F.; et al. ChemBioChem 2001, 2, 758; Tietze, L. F.; et al. Angew. Chem. Int. Ed. 2006, 45, 6574; Wang, Y.; et al. Bioorg. Med. Chem. 2003, 11, 1569; Jeffrey, S. C.; et al. J. Med. Chem. 2005, 48, 1344; Kline, T.; et al. Mol. Pharmaceut. 2004, 1, 9; Hay, M. P.; et al. J. Med. Chem. 2003, 46, 5533; Tercel, M.; et al. J. Med. Chem. 2003, 46, 2132; Gieseg, M. A.; et al. Anti-Cancer Drug Design 1999, 14, 77; Hay, M. P.; et al. Bioorg. Med. Chem. Lett. 1999, 9, 2237; Atwell, G. J.; et al. J. Med. Chem. 1999, 42, 3400; Atwell, G. J.; et al. J. Org. Chem. 1998, 63, 9414; Atwell, G. J.; et al. Bioorg. Med. Chem. Lett. 1997, 7, 1493; Townes, H.; et al. Med. Chem. Res. 2002, 11, 248; Boger, D. L.; Garbaccio, R. M. J. Org. Chem. 1999, 69, 8350).